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Intramolecular Long‐Distance Nucleophilic Reactions as a Rapid Fluorogenic Switch Applicable to the Detection of Enzymatic Activity
Author(s) -
Baba Reisuke,
Hori Yuichiro,
Kikuchi Kazuya
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201406093
Subject(s) - fluorophore , nucleophile , chemistry , intramolecular force , lysine , electrophile , transesterification , enzyme , combinatorial chemistry , derivatization , fluorescence , chemoselectivity , amino acid , stereochemistry , organic chemistry , biochemistry , catalysis , physics , high performance liquid chromatography , quantum mechanics
Long‐distance intramolecular nucleophilic reactions are promising strategies for the design of fluorogenic probes to detect enzymatic activity involved in lysine modifications. However, such reactions have been challenging and hence have not been established. In this study, we have prepared fluorogenic peptides that induce intramolecular reactions between lysine nucleophiles and electrophiles in distal positions. These peptides contain a lysine and fluorescence‐quenched fluorophore with a carbonate ester, which triggers nucleophilic transesterification resulting in fluorogenic response. Transesterification occurred under mild aqueous conditions despite the presence of a long nine‐amino‐acid spacer between the lysine and fluorophore. In addition, one of the peptides showed the fastest reaction kinetics with a half‐life time of 3.7 min. Furthermore, the incorporation of this fluorogenic switch into the probes allowed rapid fluorogenic detection of histone deacetylase (HDAC) activity. These results indicate that the transesterification reaction has great potential for use as a general fluorogenic switch to monitor the activity of lysine‐targeting enzymes.